Yang, C. C. | bioRxiv Science

bioRxiv2025

Cocaine Blocks Cholinergic Activity in the Medial Habenula Prior to But Not After Induced Preference for the Drug

Descending projections from the medial habenula potently influence brainstem systems associated with reward and mood. Relatedly, the ventral, cholinergic segment of the nucleus has been linked to nicotine and cocaine addiction. Here we report that cocaine has no effect on baseline firing in the ventral medial habenula but entirely blocks the self-sustained activity initiated by endogenous acetylcholine. This effect was not altered by antagonists to dopamine receptors and thus presumably reflects a direct action on cholinergic receptors. Remarkably, cocaine had no effect on endogenous cholinergic activity in mice that had been extinguished from an induced cocaine preference. In all, the drug has potent effects, albeit through an exotic mode of action, on the medial habenula and these are eliminated by prior experience with the drug. These results describe a novel target for cocaine that is plausibly related to the psychological effects of the drug, and an unexpected consequence of earlier use.

neuroscience↗

bioRxiv2022

Normative Sex Differences in Cognition and Morphometric Brain Connectivity: Evidence from 30,000+ UK Biobank Participants

There is robust evidence for sex differences in domain-specific cognitive performance in the general population, where females typically show an advantage for verbal memory (VM), while males tend to perform better on tasks of spatial memory (SM). Sex differences in brain structure and connectivity are also well-documented and may provide insight into sex differences in cognition. In this study, we examined sex differences in cognition and morphometric brain connectivity of a large healthy sample (N = 31,180) from the UK Biobank dataset. Using T1-weighted magnetic resonance imaging (MRI) scans and regional cortical thickness values, we applied jackknife bias estimation and graph theory to obtain subject-specific measures of morphometric brain connectivity, hypothesizing that sex-related differences in brain network global efficiency, or overall connectivity, would underlie observed cognitive differences. As predicted, females demonstrated better VM performance and males showed an advantage in SM. Females also demonstrated faster processing speed, with no observed sex difference in executive functioning. Males tended to have higher global efficiency, as well as higher regional connectivity (nodal strengths) in both the left and right hemispheres relative to females. Furthermore, higher global efficiency in males was found to mediate observed sex differences in cognition, predicting poorer verbal memory performance, better spatial memory, and slower processing speed in males. These findings contribute to an improved understanding of the way biological sex and differences in cognitive performance are related to morphometric brain connectivity as derived from graph-theoretic methods.

neuroscience↗